The Pharmaceutical Industry at a Glance Analysis of Countries Participating in International Clinical Trials in Recent Years -Based on ClinicalTrials.gov, a clinical trial registration system

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Shinichiro Awamura, Senior Researcher, National Institute of Biomedical Innovation Policy

In Policy Research Institute News No.57, we reported that the drug lag has been improving in recent ^years1) based on the status of the world's top 300 products in terms of sales launched in Japan, the U.S., and Europe. The report cited the shortening of the review period in Japan (PMDA) to a level similar to that in the U.S. (FDA), as well as the increase in the number of global clinical trials conducted in Japan since the issuance of the "Basic Policy on Global Clinical Trials" by the MHLW in 2007. In FY2018, 389 (50.9%) of 764 clinical trial plan notifications were related to international joint clinical trials, accounting for the ^majority2).

Regarding international joint clinical trials, in the past, in Policy Research Institute News No. 48 (July 2016), we analyzed the status of international joint clinical trials in Japan and the number of cases based on a questionnaire survey of pharmaceutical ^companies3), but we did not compare the situation with that in other countries. In addition, Policy Research Institute News No. 41 (March 2014) compared Japan with other countries around the world for trials registered on ClinicalTrials.gov, a clinical trial registration ^system4), but did not update the data after 2012, when the number of clinical trial plans submitted for international joint trials increased rapidly.

In order to analyze how Japan and other countries around the world have been participating in international clinical trials since 2012, we conducted a survey on the number of studies conducted in each country.

The survey used the ClinicalTrials.gov clinical trial registration system operated by the National Institutes of Health (NIH) in the U.S., as in Policy Research Institute News No.41, to survey the number of Interventional Studies (Clinical Trials) registered in the system. The trials were included in the study (as of September 5, 2019) if the Phase was Phase 2 or Phase 3 and the Fund Type was registered as Industry.) For the purposes of this report, trials with two or more registered sites in two or more countries were defined as international collaborative trials, and trials with one site in one country were defined as single-country trials.

Number of ClinicalTrials.gov Registered Trials per Year

Figure 2 shows the number of trials (2000-2018) for trials registered on ClinicalTrials.gov (Phase: Phase 2 or Phase 3 trials, Fund Type Industry) by year of study start for each trial.

For both international and single country trials, the number of trials enrolled increased rapidly from 2000 to 2006 (year of study start), and then remained stable until 2018, with no significant fluctuations in either case: 800 to 900 trials for international trials and 1400 to 1600 trials for single country trials.

The 2000 revision of the Declaration of Helsinki (requiring publication of clinical research results) and the 2004 International Council of Medical Journal Editors (ICMJE) ^statement5) (studies that have not been registered in a public clinical trial publication database prior to the start of subject entry will not be accepted for publication in ICMJE member medical journals such as the Lancet) In addition to the FDA's "Clinical Trials Registration Act" of 1997 and the 2007 FDA Amendments ^Act6), the 1997 and 2007 FDA Amendments ^Act6) mandated that trials conducted by submitting an Investigational New Drug application (IND) to the FDA be pre-registered on ClinicalTrials.gov, which is believed to have increased trial registration from the United States and around the world. On the other hand, the overall number of trials has not changed since 2006, when trial registration became established, and therefore the number of Phase 2 or Phase 3 trials itself is considered to have not changed since 2006.

Number of international clinical trials/single-country trials by country

The number of trials conducted in international joint trials/single country trials (cumulative number of trials from 2000 to 2018) was calculated for each country, and the top 30 countries by international joint trials, single country trials, and total number of trials are shown in Table 1.

The United States, Germany, Canada, the United Kingdom, France, Spain, and Italy had the highest number of trials conducted in international joint trials, in that order. Among the top 10 countries, European countries (in addition to the five major countries, Eastern European countries such as Poland, Russia, the Czech Republic, and Hungary also ranked high) accounted for all but two of the North American countries, the United States and Canada, while in Asia, Korea ranked highest at 15th, Taiwan ranked 21st, and Japan ranked 28th with 1396 trials. China was not among the top 30, ranking 40th with 867 trials.

On the other hand, the U.S. had by far the largest number of single-country trials with 13,153 trials, about 10 times the number of trials registered in Japan, the second-ranked country. Other than the U.S., Japan, Germany, China, Canada, and South Korea were the most common countries, in that order, while Asian countries had a relatively large number of single-country trials registered on ClinicalTrials.gov.

In terms of the total number of trials (international joint trials + single-country trials), the United States had the largest number of both international joint trials and single-country trials, followed by European countries (Germany, the United Kingdom, France, Spain, and Italy) and Canada, which had the largest number of international joint trials, while Japan and China ranked 16th and 23rd, respectively.

The U.S. had a large number of single-country trials as well as international trials, even though ClinicalTrial.gov is the country's own clinical trial registration system. In contrast, in European countries, the number of trials registered on ClinicalTrial.gov was overwhelmingly larger for international trials than for single-country trials. Although it is possible that single-country trials are not intended for submission to the U.S. (FDA) and are not registered on ClinicalTrial.gov, the U.S. clinical trial registration system, Europe is located in the same economic zone (European Union) and is close to other countries, and the EMA's central review system has been adopted. However, the European countries are located in the same economic zone (European Union) and the EMA has adopted a centralized review system, so it is possible that many so-called "European joint trials" are conducted in two or more European countries. In addition, since the early 2000s, when many international joint clinical trials began to be conducted worldwide, major contract research organizations (CROs) in the U.S. have strongly promoted the implementation of trials (case acquisition) in Eastern European countries such as Poland and the Czech ^Republic7). Japan also often conducts joint trials in Asia with other Asian countries such as South Korea, Taiwan, and ^Singapore8), but the number of such trials itself is considered to be smaller than in Europe.

Number of Trials of International Clinical Trials in Major Countries Yearly

Figure 3 shows the annual number of studies of international clinical trials by major country (the U.S., Japan, China, Germany, France, and the U.K.), and Figure 4 shows the ratio of such studies to the total number of international clinical trials.

As noted above, the U.S. saw a rapid increase from 2000 to 2006, in line with the increase in registrations to ClinicalTrial.gov, with 549 trials in 2006, and a gradual rise since then, to 684 trials in 2018. This represents 77.5% of all international trials registered on ClinicalTrial.gov. For Germany and France, the increase has ceased since 2006, with Germany averaging 400 trials per year (about 45% of the total) and France averaging 320 trials per year (35-40% of the total). However, both Germany and France have seen an annual increase in the number of studies participating in international clinical trials conducted jointly with the U.S., while the number of studies in international clinical trials conducted solely in European countries has been declining (data not shown.). In the U.K., the number of trials from 2006 to 2011 remained at around 300 (about 30% of the total), but since 2012, the number has slightly increased to around 350 (40-45% of the total). Japan, on the other hand, had 19 examinations in 2006, but has continued to increase since then, increasing about 10-fold to 174 examinations per year (19.7% of the total) in 2018. China had increased from 57 trials in 2006 to 83 trials (9.4% of the total) in 2018, but its participation in international collaborative trials had not increased as much as in Japan. However, China's "Opinions on Deepening Reform of the Review and Approval System and Recommendations for Pharmaceutical and Medical Device Innovation" (Agency letter [2017] No. 42), including optimization of clinical trial review procedures (an IND is considered approved if it is not rejected by the Chinese authorities within a certain period after IND submission), priority review, and acceptance of overseas data, etc. With the rapid increase in the promotion of new drug development, as evidenced by the issuance of the Opinions on Regulatory Reform jointly by the Chinese Central Regulatory Commission and the State Council Regulatory Commission in October 2017, we believe that China's participation in international joint clinical trials is likely to increase in the future.

Analysis of Nationality of Companies Conducting Multinational Clinical Trials in Japan

Next, the 1396 international clinical trials conducted in Japan (study start years 2000-2018) selected in the survey were analyzed using "Sponsor/Collaborators" information registered on ClinicalTrial.gov to determine the nationality of the companies conducting these trials. The results show that Japanese companies are more likely to conduct trials with foreign companies than foreign companies. The results showed that Japanese companies were sponsors/collaborators in only 13.8% of all global clinical trials, including those conducted in collaboration with overseas companies. In addition, the annual trend shows that although the number of international clinical trials conducted in Japan is increasing, the percentage of trials in which Japanese companies are involved has not changed significantly, ranging from 10 to 20%, indicating that Japanese participation in international clinical trials conducted by overseas companies, mainly global megapharmaceutical companies, is increasing, The main reason for the increase in the number of international clinical trials conducted in Japan was Japan's increasing participation in international clinical trials conducted by overseas companies, mainly global megapharmaceutical companies.

Summary

In past reports, we have reported that the number of international joint clinical trials conducted in Japan has been increasing in recent years, but this time we conducted a new survey based on clinical trials registered on ClinicalTrial.gov and found that the number of international joint clinical trials conducted in Japan has continued to increase since 2014, and that the number of such trials is also increasing compared to other major countries. The study found that the number of global clinical trials conducted in Japan has continued to increase since 2014, and the increase is more pronounced than in other major countries, with Japan now participating in approximately 20% of the global clinical trials conducted around the world.

With the increase in the number of global clinical trials conducted in Japan, more and more innovative drugs are being submitted simultaneously in Japan, the U.S., and Europe, which is a desirable trend for eliminating the drug lag. On the other hand, these international clinical trials are currently conducted mainly by global megapharmaceutical companies in Europe and the U.S. In order for Japanese companies to create innovative drugs globally and grow in the future, it will be important to actively promote international joint clinical trials.

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